Keywords
Sturge-Weber syndrome - febrile seizure - neurosurgery
Introduction
Sturge-Weber syndrome (SWS) is a neurovascular condition with a very low incidence,
affecting one of 20,000 to 23,000 live-births.[1] This condition derives from a post-zygotic somatic mutation of GNAQ gene,[1]
[2] located in chromosome 9,[3] responsible for cellular proliferation and inhibition of apoptosis. This gene is
mostly expressed in the brain and lung; when is altered, it leads to an uncontrolled
tissue proliferation, particularly of the endothelial cells.[4] Clinical features of this syndrome include postcapillary and venous malformation
which might affect different tissues including brain, skin, and eye,[3] producing a classic cutaneous lesion described as Port wine birthmark, usually located in the territory of either the frontonasal prominence with or without
compromising the optic vesicle area,[5] seizures, usually focal seizures with or without secondary generalization, moderate
to severe headache, and glaucoma.[1]
[2] Based on the features, Roach classified SWS into three types[6]: type I, which is the most common (classic) presentation including both cutaneous
and leptomeningeal capillary malformation (LCM), with or without glaucoma, type II
includes the presence of a port-wine stain with glaucoma but without leptomeningeal
involvement, and type III, the least common presentation, characterized by LCM without
cutaneous or ocular affection. Currently, this type of SWS is considered an incidental
diagnosis, and mostly done during adulthood. The purpose of this article is to present
a case report of a type III SWS and review the clinical features of this rare entity.
Clinical Case
A Hispanic 4-years and 1-month old female was brought by her mother to the emergency
room because she presented a generalized tonic-clonic seizure, staring spell along
with urinary incontinence, apparently lasting 30 minutes. In the emergency room, the
patient received midazolam (0.1 mg/kg) followed by a phenytoin load (15 mg/kg) which
successfully stopped the seizures. By the history, in the preceding 24 hours, the
patient had had upper respiratory symptoms including clear rhinorrhea, cough, and
intermittent fever, with quantified temperature of 38.4°C (101.2°F), managed with
acetaminophen.
Based on the information provided by the mother and the clinical findings, a parainfectious
status epilepticus was considered, and the patient was admitted to the pediatric unit.
At admission, she was confused, on supplementary oxygen, with normal vital signs.
Cardiopulmonary auscultation showed no pathological findings. Neurological examination
showed a somnolent but arousable patient, oriented in person, and responsive to her
mother's voice. Pupils were 4 mm and briskly reactive to light. Muscle bulk and tone
were normal. Strength was full bilaterally. Reflexes were 2+ and symmetric at the
biceps, triceps, knees, and ankles. Plantar responses were flexor. The patient did
not have any relevant perinatal or birth condition in her medical records. After she
was 6-months old, she had two febrile seizures and after studies, including an electroencephalogram
(EEG) whose result was normal, she was diagnosed with a complex febrile seizure managed
with valproic acid 15 mg/kg/d.
In her blood work-up ([Table 1]), lymphocytosis was observed, a respiratory viral panel was negative and her valproic
acid values were in subtherapeutic range. A head computed tomography (CT) ([Fig. 1], top line) showed atrophic changes in the right hemisphere and subcortical irregular
calcifications of the same side, suggesting a structural etiology of the seizures,
compatible with SWS.
Fig. 1
Top line: head CT sequence in axial cuts, showing multiple subcortical and irregular calcifications
dispersed in the right brain hemisphere and the calcarine gyrus, along with the tram-track sign (red arrow).
Bottom line: head magnetic resonance (MRI), contrast enhancing images showing leptomeningeal
malformations with brain parenchymal loss (blue arrow), and leptomeningeal thickening (orange arrow). Head MRI, T2 sequence in coronal cuts, showing leptomeningeal capillary malformations
(white arrows arrows) along the right hemisphere.
Table 1
Patient́s work-up
|
Parameter
|
Obtained value
|
Reference value
|
Reference unit
|
|
Creatinine
|
0.3
|
0.5–1.5
|
mg/dL
|
|
Ureic nitrogen
|
10
|
8–20
|
mg/dL
|
|
Na+
|
140
|
135–150
|
mEq/L
|
|
K+
|
4,2
|
3.5–5
|
mEq/L
|
|
Cl−
|
105
|
96–106
|
mEq/L
|
|
Mg2+
|
2
|
1.6–2.3
|
mEq/L
|
|
CPR
|
<0,5
|
1
|
mg/dL
|
|
Hemogram
|
|
|
|
|
Leucocytes
|
12.2
|
5.5–15.5
|
× 103 cell × L
|
|
Neutrophils
|
2.56
|
1.5–8.5
|
× 103 cell × L
|
|
Lymphocytes
|
8.54
|
2.0–8.0
|
× 103 cell × L
|
|
Hemoglobin
|
12.5 g
|
12–16
|
g/dL
|
|
Hematocrit
|
38
|
36–8
|
%
|
|
Platelets
|
340
|
150–450
|
× 103 cell × L
|
|
Urinalysis
|
|
|
|
|
pH
|
6.0
|
5–7
|
–
|
|
Density
|
1.007
|
1.005–1.030
|
–
|
|
Proteins
|
0
|
0–14
|
mg/dL
|
|
Leukocyte esterase
|
Negative
|
Negative
|
–
|
|
Nitrites
|
Negative
|
Negative
|
–
|
|
Epithelial cells
|
1
|
1–2
|
Por campo
|
|
Red blood cells
|
0
|
0–1
|
Por campo
|
|
Respiratory panel virus
Adenovirus, Influenza A y B, VSR, human metapneumovirus y parainfluenza 1, 2 years
3
|
Negative
|
–
|
–
|
|
Valproic acid
|
37.3
|
50–100
|
µg/mL
|
|
PCR* SARS CoV2
|
Negative
|
–
|
–
|
|
TORCH work-up
|
Negative
|
–
|
–
|
Abbreviations: Na+, sodium, K+, potassium; Cl−, chloride, Mg2+, magnesium; CPR, C-reactive protein; RSV, respiratory syncytial virus; PCR*, protein
chain reaction; TORCH, Toxoplasmosis (VDRL), Rubella, Cytomegalovirus, Herpes (IgM
and IgG) and Human Immunodeficiency Virus (HIV) (Third generation ELISA).
She was evaluated by pediatric neurology, who noted the absence of any port wine stain
on physical examination. The valproic acid dose was increased to 30 mg/kg/d and levetiracetam
added with a target dose of 20 mg/kg, and acetyl salicylic acid with dose of 5 mg/kg/d.
Additionally, a contrast-enhanced head magnetic resonance ([Fig. 1], bottom line) was obtained. An EEG was performed whose did not show any abnormalities,
and antibody testing for cytomegalovirus and toxoplasma was negative ([Table 2]). Pediatric ophthalmology considered she had a low risk for developing glaucoma,
considering the SWS type (III).
Table 2
Publications presenting a SWS type III in the pediatric population
|
Authors
|
Sex
|
Agea
|
Main findings
|
|
Zanzmera et al[7]
|
M
|
9
|
Patient with normal birth and development, who presented complex focal seizures since
he was 9 mo. Those seizures were managed and controlled with valproic acid and clobazam
during his initial 3 y. But later, despite he was on medication, he started with partial
complex seizures along with central vertigo and throbbing headache. Neurological,
ophthalmological, and general physical exam did not show any pathological findings.
EEG revealed right posterior head region spike and wave discharges and hCT scan showed
focal cortical atrophy over the right parietal region and gadolinium contrast revealed
LMC over the same region. Management with clobazam and oxcarbazepine was administered,
with great medical response and the patient was seizure-free in his 6-mo follow-up.
|
|
Mukherjee et al[8]
|
F
|
3
|
Patient with normal birth and development, presented in the ER with afebrile right-sided
complex partial seizures since he was 1 year old, without improvement after management
with phenytoin. During her hospitalization, EEG showed epileptiform paroxysmal burst
of discharges with hypsarrhythmia with significant cortical dysfunction, predominantly
involving left hemisphere, and her hCT showed gyral thickening, gyriform enhancement,
and focal calcification at left frontoparietal region with diffuse edema and mass
effect and her bMRI showed left frontal, parietal, and occipital LMC with calcifications.
She was discharged with valproate acid with no episodes of seizures.
|
|
Jordan et al[9]
|
M
|
9
|
Patient presented to the ER with severe throbbing left temporal headache and vomiting.
His medical records showed a similar episode when he was 6 years old. In that episode,
he had the same characteristics of the headache, along with vomiting but with a prolonged
generalized seizure, requiring orotracheal intubation. The working diagnosis at that
time was encephalitis, however, spine fluid and hCT were within normal values, and
he was discharged without further complication 1 wk later. On assessment in the current
episode, he scored 15/15 on the GCS and had an unremarkable systemic examination.
hCT contrast showed focal areas of cortical/subcortical calcification in the left
occipital lobe, initially considered as postencephalitic laminar calcification, but
radiology described as pial capillary malformation. The patient persisted with the
headache despite the analgesic management and after serial evaluations made by neurology,
a right-sided homonymous hemianopia was found; based on the clinical features he received
the diagnosis of SWS type III. Eight days later after being discharged he was brought
to the ER with recurrence of the headache along with sudden acute confusion and decreasing
conscious level; the diagnosis at that time was a complex partial seizure, managed
with phenytoin. He was discharged managed with levetiracetam. Headache improved but
the visual defect remained.
|
|
Gururaj et al[10]
|
F
|
12
|
Patients were born to consanguineous parents, with normal birth and development. When
she was 2 years old, she began with brief, generalized tonic clinic seizures with
fever, and was started on phenobarbital as prophylaxis. These episodes last until
she was 5 years old. When she was 7 years old, she experienced afebrile seizures,
the EEG showed spike-wave activities over the left occipital area with secondary generalization,
and the hCT showed a cortical curvilinear calcification in the left parieto-occipital
area associated with surrounding leptomeningeal hypervascularity. At that time, she
was managed with carbamazepine with poor adherence. When she was 12 years old, she
was admitted in status epilepticus, controlled with diazepam, bMRI showed an obvious
leptomeningeal blush in the polar area of the occipital lobe, with deep veins draining
posteriorly into the left lateral ventricle. She was restarted on carbamazepine with
proper dose, with no further seizure episodes.
|
|
Martínez-Bermejo et al[11]
|
M
|
12
|
Patient without intellectual deterioration, with a previous diagnose of epilepsy.
After a hard-managing crisis, hCT showed right temporal and occipital atrophy along
with calcifications at the same level. bMRI showed LCM and calcification in the same
level described in the CT. The EEG showed spike focal activity in the right parieto-occipital
region.
|
|
F
|
8
|
Patient without intellectual deterioration, with a precedent of epilepsy managed with
valproic acid. A new work-up set requested by pediatric neurology included an EEG,
showing interhemispheric asymmetry and low electric potential in the left hemisphere.
hCT showed a left occipital paramedian calcification, and the bMRI showed LCM in the
left occipital region.
|
|
M
|
11
|
Patient evaluated due to difficulties for learning. EEG showed a slight decrease in
the amplitude of the potentials registered in the right hemisphere. hCT showed a cortical/subcortical
calcification in the right occipital region, and the bMRI showed hypertrophic veins
in the right parietal and occipital region.
|
Abbreviations: bMRI, brain magnetic resonance; EEG, electroencephalogram; ER, emergency
room; M, masculine; F, feminine; GCS, Glasgow Coma Score; hCT, head tomography; LCM,
leptomeningeal capillary malformations; *Age in years, yo, years old.
Finally, the patient was evaluated by the pediatric neurosurgery department, who felt
that based on the extent and location of the LCM, she was not a good surgical candidate.
She was discharged home after 2 weeks with occupational therapy and pediatric neurology
follow-up. At follow-up appointments the second and fourth week after being discharged,
she had no additional convulsive episodes.
Discussion
This case shows a patient with a convulsive syndrome hard to characterize, with normal
neurodevelopment, an EEG without alterations, with a final diagnosis of a SWS III
after blood work-up and imaging studies.
The prevalence of this SWS type is very low in the pediatric population, in fact,
based on the available reports in the main databases, it cannot be established. Literature
search was performed in Medline, SCOPUS, and PubMed searching for SWS type III in
population under 18 years old, finding only five publications, reported in [Table 2].
Initially, the Port wine birthmark was considered the pathognomonic sign of the SWS,
given the fact that in different case series up to 8% of the patients with that cutaneous
lesion presented a SWS.[12] However, in the type III SWS, the absence of typical clinical features or complications
like cosmetic[3] or visual,[13] creates a diagnostic challenge, explaining the uncertain prevalence of this subtype.
Furthermore, the clinical presentation of this SWS subtype is in the context of seizures
or headache, most of them presenting as complex febrile seizures or migraine headaches,
that only after imaging and electroencephalographic studies the diagnosis of this
condition could be made.[11]
Seizures are common in SWS, considering that LCM acts like a structural epileptogenic
focus, however, the detection in the EEG may only be made when it affects a large
brain area.[14] EEG findings correlate with the LCM size, because at the beginning there is a slight
vascular dilation and later dysgenesis of the superficial venous system with no changes
in the EEG, but later there will be shunts with the deep system, leading to venous
dilation, flow stasis, and chronic ischemia, presented in the imaging as linear cortical
calcificacitions, known as tram-track sign, with features in the EEG including from
focal asymmetry to epileptiform pattern.[15]
Imaging for characterization of SWS often starts with tomography, useful in this case
because it helps to show calcifications. However, based on the ionizing radiation
and limitation in the evaluation of brain parenchyma, the preferred method to evaluate
this condition is contrast-enhanced magnetic resonance imaging,[4]
[16]
[17] finding in the early phases of the SWS a transitory abnormal white matter signal,
moreover, leptomeningeal enhancement is found because it is the most affected region,
and limited diffusion can be found if there have been ischemic episodes. Late disease
shows an increased signal in the T2 sequence related with gliosis and low enhancing
of the pia mater and secondary brain parenchyma atrophy.[17]
Due to the unpredictability of the clinical course of the SWS type III, it is both
challenging to diagnose and treat, based on the wide clinical spectrum, because it
can start from being asymptomatic or a migraine-like headache,[1] to medically intractable seizures,[18] along with hemiparesis,[5] and cognitive impairment.[19]
Epilepsy in patients with SWS is usually focal but may secondarily generalize,[18] with an incidence up to 90% in patients in SWS type I; however, in a great proportion
of patients the debut could be as status epilepticus, with a long remission time between
seizures.[12]
[18] In the current management, prophylaxis should be included because several studies
have shown its importance to reducing the risk of cognitive impairment.[18]
[19] The m-Tor inhibitor agent sirolimus in combination with low-dose aspirin or phenobarbital
has been successfully used. Medical management of seizures often has to be aggressive,
and has included oxcarbazepine, because of a favorable rate of adverse effects reported,[4] in combination with carbamazepine or levetiracetam, particularly useful in patients
with bilateral brain involvement; in cases when the patients have migraine-like headaches
management could be complemented with valproic acid or topiramate.[1]
[4] Regarding surgical management, it is considered to have prophylactic potential,[16]
[17] and in up to 50% of the patients, hemispherectomy or a functional hemispherectomy
can be performed with great outcomes regarding epilepsy control.[12]
[16]
[20] It was not considered in this patient because she had control of her epilepsy episodes.
Management should also include anti-aggregation, usually with acetyl salicylic acid
in dose between 3 and 5 mg/kg/d, because it helps to control seizures by diminishing
the blood stasis[12] and may help to avoid hemiparesis and stroke-like episodes.[16]
[20]
Considering the complexity of the SWS, management should be addressed by a multidisciplinary
team,[16]
[19]
[20] where a proper clinical approach by the emergency and general pediatric services
may lead to a better outcome, based on the early start of proper management. Quality
of life should be continuously assessed because main goals include involvement with
family and peers, reducing adverse effects of the anticonvulsants, and emotional support.
Interestingly, patients who started antidepressants had worst cognitive development.[1]
[6]
[17]
Conclusion
SWS is a rare neurocutaneous disease, usually diagnosed in patients with pathognomonic
features, however, it is important to know that type III SWS exists and represents
a challenging diagnosis, leading to a time-race for starting proper management, considering
that the outcome includes a better quality of life, a higher cognitive result, and
reduced morbimortality.
